Lactic acidosis, occurring in the absence of the usual predisposing factors and prior to the appearance of cardiovascular decompensation and decreased tissue perfusion, is a poorly understood and challenging problem. For reasons that are not particularly clear patients with diabetes mellitus, either because of a metabolic defect or the presence of significant vascular disease, are unusually susceptable to the development of idiopathic lactic acidosis. A better understanding of the factors that control lactic acid production and lactate utilization is needed since it appears that lactic acidosis can be a result of abnormalities of one or both processes. Under ordinary circumstances the capacity of the liver to utilize lactate far exceeds the ability of other tissues to generate lactic acid and it has been suggested, without much evidence, that impaired hepatic utilization of lactate may be responsible for lactic acidosis. On the other hand since lactate utilization is a concentration dependent phenomenon decreased hepatic utilization could very well be balanced by increased lactate utilization by other tissues such that the role of the liver in lactate balance is not as important as proposed. Experiments will be undertaken in this project to evaluate the role of the liver in the pathogenesis of lactic acidosis and the relationship between diabetes mellitus and the predisposition to development of lactic acidosis. The role of the liver will be examined in an animal model in which acute vascular exclusion of the liver from the circulation can be accomplished. Lactic acid will be infused at varying rates to produce graded degrees of acidosis and the balance of lactate across various tissue beds and the degree of acidosis and the balance of lactate across various tissue beds and the degree of acidosis will be determined in the presence and absence of hepatic exclusion. These studies should clarify the role of the liver in maintaining lactate utilization in the presence of decreased hepatic lactate uptake. The effects of diabetes mellitus will be evaluated in both the acute and chronic phases of the disease in animals. Diabetes mellitus will be induced by guinea pig anti-insulin serum and/or the infusion of somatostatin with and without glucagon. The role that insulin therapy might play in the pathogenesis of lactic acidosis in decompensated diabetes will be evaluated under experimental situations in which insulin is administered to both acutely and chronically diabet (Text Truncated - Exceeds Capacity)